1354
J . Org. Chem. 1980,45, 1354-1362
Displacement of Protomeric Equilibria by Self-Association: Hydroxypyridine-Pyridone and Mercaptopyridine-Thiopyridone Isomer Pairs Peter Beak,* Johnny B. Covington, Stanley G. Smith, J. Matthew White, and John M. Zeigler Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801
Received J a n u a r y 8, 1980 Values of both self-association and protomeric equilibrium constants are reported for 2-hydroxypyridine-2pyridone, 4-hydroxypyridine-4-pyridone,and 2-mercaptopyridine2-thiopyridone isomer pairs in different solvents. These results provide quantitative evidence for significant differences in the positions of protomeric equilibria for self-associated and monomeric species. The 2-substituted isomers are associated as well-known dimers while the 4-substituted systems form oligomers. In polar and hydrogen-bonding solvents self-association is substantially reduced. Sterically hindered 2- and 4-pyridones are less associated than unhindered systems. The implication of these results, that determinations and interpretations of protomeric equilibrium should take into account the possible dominance of self-association, is discussed.
Evaluation of the effect of self-?sociation on protomeric equilibria is essential for reliable interpretation of solution data.’ In this report we detail evidence which establishes that self-association can have a dominating effect on the apparent solution protomeric equilibrium constants for 2and 4-hydroxypyridine-pyridone and 2-mercaptopyridine-2-thiopyridone isomer pairs in nonpolar media.2,3 We also report the effect of solvent and substituents on these associations. The implications of these observations are discussed as a matter of general concern for determinations and interpretations of positions of protomeric equilibria. In the preceding paper a quantitative model for the effect of molecular environment on these and related equilibria is d e ~ e l o p e d . ~ Thermodynamic and kinetic evidence for a strong hydrogen-bonding dimerization of 2-pyridone in solution has been reported and reviewed.“’ For example a t a 0.01 M concentration in benzene, 2-pyridone is 855% dimerized.8 Other pyridones have been less thoroughly investigated, but 2-thiopyridone is only slightly less associated than 2-pyridone,8pgand 4-pyridone is reported to be a trimer in chloroform.1° As early as 1968 it was noted that self-association might affect protomeric equilibrium constants of hydroxypyridine-pyridone ~ y s t e m s . ~ ~ ~However, ~~J-’~ (1) P. Beak, Acc. Chem. Res., 10, 186 (1977), and references cited therein. (2) We have used these systems as prototypes in earlier gas-phase studies. P. Beak, F. S. Fry, J. Lee, and F. Steele, J . Am. Chem. SOC.,98,
a quantitative assessment of the influence of intermolecular association on such protomeric equilibria has not been available p r e v i ~ u s l y . ~
Results Analytically pure samples of the isomer pairs 1-24 were used for protomeric and association studies. The syntheses of compounds 7-14 are described in the Experimental Section.
H
1,X= Y= Z= H 2, X = Y = Z = H 4, X = C1;Y = Z = H 3, X = C1; Y = Z = H 5, X = CH,;Y = OCH,; Z = H 6 , X = CH,; Y = OCH,; Z = H 7 , X = CH,; Y = H; 8, X = CH,; Y = H; Z = CH=CH(CH,),CH, Z = CH=CH(CH,),CH, 9, X = CH,; Y = H; 1 0 , X = CH,; Y = H; CH(CHz) 3CH3 CH(CHz),CH,
I \
s
z= I
I \
s s
s
z= I
I
171 (1976). (3) For a preliminary report of some of the work detailed herein, see: (a) P. Beak, J. B. Covington, and S. G. Smith, J . Am. Chem. SOC.,98,8284 (1976); (b) P. Beak, J. B. Covington, and J. M. Zeigler, J . Org. Chem., 43, 177 (1978). (4) P. Beak, J. B. Covington, and J. M. White, J . Org. Chem., pre-
ceding paper in this issue; P. Beak and J. B. Covington, J. Am. Chem. Soc., 100, 3961 (1978). (5) H. Tieckelmann, Chem. Heterocycl. Compd., 14, 731 (1974). (6) J. Elguero, C. Marzin, A. R. Katritzky, and P. Linda, “The Tautomerism of Heterocycles”, A. R. Katritzky and A. J. Boulton, Eds., Academic Press, New York, 1976, Supplement 1. (7) For more recent work, see: K. A. Engdahl and P. Ahlberg, J . Chem. Res. (S), 340 (1977); 0. Bensaude, “Protons and Ions Involved in Fast Dynamic Phenomena”. Elsevier, Amsterdam, 1978, pp 393-401, and references cited therein. (8) M. H. Krackov, C. M. Lee, and H. G. Mautner, J . Am. Chem. SOC., 87, 892 (1965); G. G. Hammes and H. 0. Spivey, ibid., 88, 1621 (1966). (9) N. Kulevsky and W. Reineke, J . Phys. Chem., 72, 3339 (1968). (10) R. A. Coburn and G. 0. Dudek, J . Phys. Chem., 72,3681 (1968). (11) P. Beak, J. Bonham, and J. T. Lee, J . Am. Chem. Soc., SO, 1569 (1968). (12) G. Simchen. Chem. Ber., 103,398 (1970). (13) S. T. King, W. C. Dilling, and N. B. Tefertiller, Tetrahedron, 28, 5859 (1972). (14) M. J. Cook, A. R. Katritzky, L. G. Hepler, and T. Matsui, Tetrahedron Lett., 2685 (1976).
0022-3263/80/1945-1354$01.00/0
I
CH,-CH, CH,-CH, 1 2 , X = (CH,),C,H,-p-SC,H,; 11, X = (CH,),C,H,-p-SC,H,; Y = H; Z = CO,C,,H, Y = H; Z = CO,C,,H,, 13, X = CH=CHC,H,-p-SC,H,; 1 4 , X = CH=CHC,H,-p-SC,H,; Y = H; Z = CO,C,,H,, Y = H; Z = CO,C,,H,,
H
16
15
?” X
Ay H
17, X = Y = H 19, X = H; Y = C1 21, X = Y = CH, 23, X = Y = C(CH,),
18, X = Y = H 20, X = H; Y = C1 22, X = Y = CH, 24, X = Y = C(CH,),
(15) J. Frank and A. R. Katritzky, J . Chem. SOC.,Perkin Trans. 2, 1428 (1976). The discrepancy between the results in this reference and
our work have been discussed and attributed to self-association and the single-wavelength determinations used in the Frank and Katritzky work.
0 1980 American Chemical Society
J. Org. Chem., Vol. 45, No. 8,1980 1355
Displacement of Protomeric Equilibria Table I. Changes in Ratios of Optical Densities at ,A, for Hydroxypyridine-Pyridone and Mercaptopyridine-Thiopyridone Chromophores OD,b substr 1-2c
concn, M T,a “ C 5 x 10-5 5x 100 5 x 10.’ 130 5 X 150 5x 160 1 x 10-5 3x
2x 8X 4 x 10-7
3-4e 15-16f
3 x 10.’ 13-7 5x 2 x lo-4 4 x 10-5 1X
1 x 10-5 3 x 10-3 1 x 10-4 5 x 10-6
solvent decane decane decane decane decane cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane chloroform chloroform chloroform cyclohexane cyclohexane chloroform chloroform chloroform
hmax,NH/ hmax,O~
>5 1.7
0.95 0.88 0.88
>5 >5
1.3 d l.Od l.Od
0.71 0.77 4.4
2.3 2.3 0.8 0.04
8.0 1.5 1.5
Ambient temperature unless otherwise noted. 300 and 275 nm. 310 and 278 Errors are +10%. nm. e 305 and 278 nm. 360 and 240 nm. a
Scheme I Y
Table 11. Association of Hydroxypyridine-Pyridones from Vapor Pressure Osmometry % associateda
substr concn, M solvent 1-2 1 X lo-’ chloroform 1X lo-’ chloroform 2X chloroform 1X l o - ’ chloroform 4 x lo-’ ethanol 3-4 5 X lo-’ chloroform 6X chloroform chloroform 5 X 10.’ chloroform 5 X lo-’ 5-6 1 X 10.’ benzene 1 X 10.’ tetrahydrofuran 1 X 10.’ chloroform 5 X 10.’ methylene chloride 1 x 10.’ acetonitrile 1 X 10.’ ethanol 7-8 5 X 10” methylene chloride 9-10 5 X 10.’ methylene chloride 11-12 5 X lo-’ methylene chloride 13-14 5 X 10.‘ methylene chloride 17-18 5 X lo-’ chloroform 6X chloroform 4 X methylene chloride 1X ethanol 19-20 3.9 X 1,2-dichloroethane 21-22 1 . 5 X methylene chloride 23-24 7 X lo-’ chloroform 2 X lo-’ chloroform 4 X 10.’ methylene chloride a
“C. mol mol mol mol
I
H
(tYPe 1 100 i 4 (dimer) 862 6 37
i
61 i 23i 9 1 i57 i 75i 69 38
i
6 5b 8
2 (dimer) 6 56 3c
3 (dimer) 55i: 1 I
100
It
86
i
5 5 3 2 11 50* 6 68 ?- 9 (dimer) 63 I 6 (dimer) 35 I 7 (dimer) 21 i- 5 (dimer) > 9 8 (o1igomer)d
> 90e
>9gb>f 40g 40 (oligomer)C*h >98 (oligomer)b,i
60 (oligomer)’ 30
601
Ambient temperature unless otherwise noted. 37 50 “C. Average mol wt 870 i 18. e Average wt 364 i: 78. Average mol wt 540 i 87.. g Average wt 169 I3. h,Average mol wt 1 6 3 i 1. Average wt 660 = 66. Average mol wt 339 I 4. Average wt 253 i 3. Average mol wt 345 i 4. J
Scheme I1 0
II
Y
Y
I
H
Y
The ratios of the hydroxypyridine to pyridone and mercaptopyridine to thiopyridone chromophores were determined by the ultraviolet analyses used theretofore and developed by many workers from the pioneering work of Specker and Gawrosch.*J6 For calculations of protomeric equilibrium constants (KT)the assumption that the chromophores of the OCH3 and NCH, compounds provide adequate models for free and associated OH and NH protomers was modified by inclusion of small shifts in,,A for cases in which Dewar-Urch analysis” indicated better correlation was thus achieved. It should be noted that the extremely dilute solutions, down to M, required for the investigation of 2-pyridone necessitated the construction of a spectrophotometer which allowed the use (16) H. Specker and H. Gawrosch, Chem. Ber., 75, 1338 (1942). For a review, see: S. F. Mason “Physical Methods in Heterocyclic Chemistry”, Vol. 11, A. R. Katritzky, Ed., Academic Press, New York, 1963. (17) M. J. S. Dewar and D. S. Urch, J . Chem. SOC.,345 (1957).
H
of 3-m sample and reference tubes.I8 In Table I the changing ratio in optical densities of A, for bands assigned to the NH and OH chromophores of the 1-2,3-4, and 15-16 systems is listed as a function of temperature or con~entration.’~ Equilibrium constants for association (K,,,,) obtained, in most cases, by vapor-pressure osmometry are given as ratios of mole fractions according to the treatment described by Schrier20as shown in eq 1-4, where u = l, 2, UP
=Pa K,
(1)
(18) For details, see, J. B. Covington, Ph.D. Thesis, University of Illinois, 1978, available from University Microfilms, Ann Arbor, MI. (19) The data are presented in this form in anticipation of our subsequent demonstration that a chromophore is comprised of more than one species.
J. Org. Chem., Vol. 45, No. 8,
1356
Beak et al.
1980
Table 111. Rotomeric Equilibrium Constants and Association Constants for Hydroxypyridine-Pyridone Isomers
oligomerization specific protomers
~
substr 1-2
solvent cyclohexane benzene chloroform chloroform dioxane chloroform methylene chloride benzene tetrahydrofuran ethanol acetonitrile methylene chloride methylene chloride chloroform chloroform methylene chloride ethanol toluene 1,2-dichloroethane methylene chloride chloroform methylene chloride
3-4e 5-6
10 11-12 15-1 6 18
19-20 22 23-24
a
OC.
[NH]/[YH]. e
KTU
K=~~,NH
1.6 i 0.5 >5 >5 >5 >5 0.45 t 0.3
(5.6 t (9.0 t (2.5 + (9.5 k
>5
(1.5 * 0.4) x l o 3 (5.2 * 0.3) x 10'
>5 >5 >5
(5.0 * 2.0) x 10' (5.7 * 5.0) x 1 0 (3.6 t 2.0) x 103
lo2
0.6 k 0.2
(5.3 ?: 1 . 0 ) X
2.6 * 0.5
(2.7 k 0.5) x l o 3 ( 3 t 0.7) x 104 ( 7 . 4 k 2.4) x 104
>5 >5
(6.0 k 2.0) x 1 0 (6.9 k 0.4) x 10' (9.6k 0.8) x l o 2
>5
( 4 . 8 * 1.0) x 104 (1.8 * 0.5) x l o 2 (2.1 * 0.2) x l o 3
>1
Calculated from ref 8.
27 "C. ~
37 ~
Scheme IIIa
I
21
H
26
28
29
CH3
I
H
1 a : ( 1 ) (CH,),O+BF;, CH,Cl,, room temperature, 48 h; ( 2 ) 10%aqueous NaOH. b: ( 1 ) DIBAH, toluene, -78 "C; (2) saturated aqueous NH4C1;(3) 5% H,SO,; ( 4 ) 10% aqueous NaOH. c : ( 1 ) n-BuMgI, Et,O, -10 "C;( 2 ) CH,(PhO),P+I-,HMPA, 75 "C, 2 h. d : (CH,),SiI, CHCl,, A , 24 h.
..., n, X,
= the stoichiometric mole fraction = XI
+ 2Xz
+ ... + ax,, X, = the effective mole fraction = X1 + Xz + ... + X , , and X, = the mole fraction of aggregate a.
(20) E. E Schrier, J . Chem. Educ., 45, 176 (1968).
= Xa/(XJa
-Kassoc,YH
(3)
XyH(monomer) (4) XyH(associated)
It is important to note that by this analysis the equilibrium constants are dimensionless and suitable for thermodynamic analysis. Representative association results are collected in Table 11, and equilibrium constants for association appear in Table 111.
(7 * 1 ) X l o 3 (2.4 k 1.0) x 104
~= (7 c 1)~ x 103. ~
K
1.7) X l o 6 1.0) x i o 4 1.0) x 104c 1 . 0 ) x 103d
K,,,,,
,
Discussion 2-Hydroxypyridines-2-Pyridones. The changes shown in Table I in the ratios of the chromophores for 2-hydroxypyridine (1) and 2 pyridone (2) and for 6chloro-2-hydroxypyridine(3) and 6-chloro-2-pyridone (4) as a function of dilution are inexplicable if only two isomeric species are in equilibrium. On the other hand, those changes can be readily accommodated if monomeric and dimeric species contribute to the absorptions. Qualitatively, inclusion of the well-known dimerization of 2-pyridone, shown as K a s s o c , N ~in Scheme I, with the protomeric equilibrium, represented as KT, provides a satisfactory model. The change in the ratios of chromophores is then explained if dilution shifts the associative equilibrium from the dimer, in which only the 2-pyridone chromophore is observable, to monomeric species, for which both chromophores are seen.15 If Scheme I is correct, the ratios of monomeric 1 and 2 should reach a constant value on dilution; this appears to occur at 3 X lo-' M in cyclohexane. The resulting KT value of 1.6 f 0.5 (Table~ 111) is sensibly near the gas-phase value of 0.4 f ~ ~ 0.2.2 Analysis of the dilution data allows calculation of a Kaawc,NH for 2-pyridone of 5.6 x lo6 f 1.7 X lo6 (Table 111) in cyclohexane. The change in the ratios of the chromophores of 1-2 on heating of the decane solution is also rationalized by Scheme I. In this case thermal energy decreases the association, and the chromophore ratio appears to reach a constant value because the equilibrium constant is not appreciably affected by temperature. Although 2-pyridone is too insoluble in cyclohexane to allow determination of the dilution and temperature dependence of the association constant by independent measurements, such studies could be carried out by vapor-pressure osmometry in c h l o r o f ~ r m .The ~ ~ ~change in KaasocaH for 1-2 in chloroform as a function of temperature allows calculation of a A G o m s o c , N of ~ -10 + 2 kcal/mol, a AHoaasoc,NH of -18.6 f 1.5 kcal/mol, and a ASoaasoc,NH of -40 f 4 eu for 2-pyridone in chloroform at 27-37 "C. The entropy value is close to the theoretical entropy of association of 26 eu attributable to the loss of translational degrees of freedom on dimerization.21 While 2-hydroxypyridine might also exist as a dimer in concentrated solution, such a species would not be observed in our experiments if its stability were an order of magnitude less than that of the 2-pyridone dimer. The association of 6-chloro-2-hydroxypyridine-6chloro-2-pyridone, a system in which both 3 and 4 can be o b s e r ~ e d , ~isJ particularly ~ J ~ ~ ~ ~ informative. The ratio of (21) K. B. Wiberg, "Physical Organic Chemistry", Wiley, New York, 1964, Chapter 2. The difference between the calculated and observed values could be attributed t o additional loss of motion in the dimerized
species. (22) A. R. Katritzky, F. A. Popp, and J. D. Rowe, J . Chem. SOC. E, 562 (1966); A. R. Katritzky, J. D. Rowe, and S.K. Roy, ibid., 758 (1967); E. Spinner and J. C. B. White, ibid., 991 (1966); E. M. Peresleni, M. Y. Uriskaya, V. A. Loginova, Yu. N. Sheinker, and L. N. Yukhortov, Dokl. Akad. Nauk SSSR, 183, 1083, 1102 (1968).
J . Org. Chem., Vol. 45, No. 8, 1980 1357
Displacement of Protomeric Equilibria
A
The case of 11-12 can be used to illustrate the value of obtaining both association and protomeric equilibrium data in an analysis of equilibrium energetics. From ultraviolet spectra and vapor-pressure osmometry in methylene chloride and the assumption that the hydroxypyridine is the species 25, as previously suggested for other
DIMER?
I
i
i
0cldnSS
I
\
25
250
300
X
350
(nm)
Figure 1. Ultraviolet spectrum of 3-4 in chloroform at a lo-’ M concentration.
the monomers, determined at high dilution, provides a basis from which analysis of the spectral and osmometric data a t higher concentrations can be dissected into the protomeric and association constants. The data cannot be fit by a model in which only one dimer is present, and we propose the existence of at least two dimers as shown in Scheme I and Table 111. The contributions to the ultraviolet spectra by the different protomers of Scheme I are shown in Figure 1. This rationale is the most economical model; however, it should be noted that although the data require a t least two dimers, one of which must be a symmetrical dimer of 3, the other could be the symmetrical dimer of 4 as shown or a mixed dimer of 3-4. Our data does not, of course, exclude three dimers. The different dimers of 3-4 provide an interesting case of hydrogen bonding in different double potential wells. The self-association association of 2-pyridone is known to be significantly affected by solvent. Free energies of association of‘2 are 9 f 1 kcal/mol in cyclohexane, 6 f 1 kcal/mol in benzene, 5 f 1 kcal/mol in chloroform, and 2 f 1 kcal/mol in dioxane.$r8 A similar trend is shown by the decreasing association of 4-methoxy-6-methyl-2pyridone (6) in the series benzene, tetrahydrofuran, ethanol, and acetonitrile as shown in Tables I1 and 111. The two factors which seem important in determining these orders are the ability of the solvent to stabilize the different dipoles and to participate in hydrogen b ~ n d i n g . ~ - ~ The effect of 3- and 6-substituents on self-association of 2-pyridones is illustrated by examination of the data in Tables I1 and I11 for the series 2, 4, 6, 8, 10, 12, and 14.24 The fact that 6-chloro-2-pyridone (4) is a factor of 3 less associated than is 2-pyridone (2) in chloroform and that 6-methyl-4-methoxy-2-pyridone (6) is a factor of 60 less associated than is 2 in benzene shows that 6-substitution can decrease a s s o c i a t i ~ n . Comparison ~~ of the association of the 3-substituted 6-methyl-2-pyridones 8 and 10 with 6 in methylene chloride shows a further decrease in association due to additional substitution at the 3-position. The 3-carboalkoxy-&alkyl-2-pyridones12 and 14 also show further reduction in association relative to 10. (23) In reference 3a K T was incorrectly given as the inverse. We are grateful to Professor 0. Bensaude for calling this error to our attention. (24) Compounds 7-14 were available from another study: J. M. Zeigler, Ph.D. Thesis, University of Illinois, 1979, available from University Microfilms, Ann Arbor, MI. (25) A chloro group has a lower A value than does a methyl group, but both groups have similar van der Waals radii. E. Eliel, “Stereochemistry of Carbon Compounds”, McGraw-Hill, New York, 1962, p 236; L. Pauling, “The Nature of the Chemical Bond”, 3rd ed., Cornel1 University Press, Ithaca, NY, 1960, pp 257-64.
3-carboxy-substituted 2 - ~ y r i d o n e s >the ~ ~values for KT and Kassw,NH of 2.6 f 0.5 and (5.3 f 1.0) X lo2 shown in Table I11 are obtained. Thus while the lower self-association of 11-12 does reflect a decrease in the association of the 2-pyridone protomer 12 relative to that of 10, by a factor of 7 , the shift of the protomeric equilibrium, by at least a factor of 8, is revealed only by the complete analysis. 2-Thiolpyridine-2-Thiopyridone. The ultraviolet spectra for 15-16 in cyclohexane and chloroform as shown in Table I change with concentration in a manner attributable to an association of 16 analogous to that described for 2 in Scheme I. While dilutions of M are required to avoid the complications of self-association in the hydrocarbon solvent, the K, for 6 (Table 111) in chloroform suggests that the M solutions normally used for ultraviolet spectroscopy would be suitable for study of monomeric species in most other solvents. At the higher concentrations used with other spectral methods, however, displacement of the apparent position of protomeric equilibrium in favor of the NH form could be caused by association. As shown in Table 111, vapor-pressure osmometry shows 16 to be somewhat less associated than 2 as has been previously 4-Hydroxypyridines-4-Pyridones.Even at M in cyclohexane the ultraviolet spectrum of the 4-hydroxypyridine (17) and 4-pyridone (18) system shows only the chromophore of 18. This appears to be in contradiction to our estimate that 17 should be the overwhelming isomer in this equilibrium in nonpolar media.’ However, in view of the demonstration that self-association can control the apparent value of KT for 2-pyridones and the suggestion that 4-pyridone is associated,10we have reinvestigated the association of 18. Limited solubility precluded measurements in cyclohexane, but we find 18 to be very strongly oligomerized in chloroform. For example at 0.025 M the modal association number is 7.27 The model suggested by this result is shown in abbreviated form in Scheme I1 with the calculated association constants given in Table 111. The extent of self-association of 18 in cyclohexane is presumably even more extensive than in chloroform. Thus, determination of the protomeric equilibrium constant between monomers from the ratios of the chromophores even in highly dilute hydrocarbon solution is not possible, and our estimate that monomeric 17 should be favored by at least lo5 over monomeric 18 in the vapor phase or in hydrocarbon solution is not disproven.’ An assumption of the model in Scheme I1 is that the equilibrium constant for the association of two monomeric species is the same as that for addition of a monomer onto an oligomer, i.e., (26) T. Kitagawa, S. Mitzukami, and E. Hirai, Chem. Pharm. Bull., 26, 1403, (1978).
(27) While repetitive measurements do appear to show that the free energy of the hydrogen bond in 18 is somewhat greater than that of 2 in chloroform, the values are within experimental error, and our earlier statement3bregarding the somewhat greater aggregation of 18 is hereby corrected.
Beak et al.
1358 J . Org. Chem., Vol. 45, No. 8, 1980
K1, = Knq+l. It seems possible that K1,2I Kn,+, since such an order is found in amide association,2s and hydrogen bonding should be more favorable in a molecule already polarized by prior association. Our attempts to measure the necessary constants for 19-20, a system in which both isomers can be observed,29have not been successful. The hydrogen-bonding oligomerization of 18 is high in chloroform and methylene chloride but is substantially reduced in ethanol as shown in Tables I1 and 111. Once again the solvent effect can be rationalized, in part, in terms of the hydrogen-bonding ability of the solvent. The effect of steric hindrance on the association of 4pyridones can be assessed by the data for 18,22, and 24 in methylene chloride shown in Tables I1 and 111. While 18 and 22 are similarly oligomerized there is a 2 orders of magnitude reduction in the association of 24. Apparently tert-butyl groups are needed in the 4-pyridones to provide sufficient steric hindrance around the position of hydrogen bonding to interfere with association.m It is pertinent that in cyclohexane the ultraviolet spectrum of 23-24 shows only the hydroxypyridine 23 to be present. That result provides support for our above contention that an unassociated 4-pyridone-4-hydroxypyridine in cyclohexane should favor the latter form in the absence of other perturbations. Conclusions The most important conclusion to be drawn from this work is that self-association of hydroxypyridine-pyridone and mercaptopyridine--thiopyridone isomers can significantly shift the apparent protomeric equilibrium between the isomers. In the case of 2-hydroxypyridine (1) and 2-pyridone (2) in cyclohexane the comparable energies of the monomeric protomers is obscured by the preferential self-association of 2 to the point that only the chromophore of the latter is observed unless the dilution is greater than M. For 2-mercaptopyridine (15) and 2-thiopyridone (16) both isomers can be observed in cyclohexane and chloroform in dilute solutions, but the equilibrium constants calculated a t higher concentrations would be erroneous if assigned to the isolated protomers. In the case of 4-hydroxypyridine (17) and 4-pyridone (18) in cyclohexane it appears that only an oligomer is seen, and the shift in the equilibrium constant relative to the monomeric species is estimated to be 5 orders of magnitude. These observations are well precedented. The strong self-association of the pyridones is ~ell-knownl-’~ and consistent with associative structures of a m i d e ~ . ~ ~ Also Bl pertinent are the recent studies of Bensaude and Dubois, who find that the protomeric equilibrium of 2-hydroxypyridine-2-pyridones is shifted in favor of the amide by complexation with water or sodium ion.32 Effects of self-association on the protomeric equilibrium of amides,33 ~~~
~
(28) In the case of oligomerization of amides it has been found that the equilibrium constant for association of two monomers is less than that for association of a monomer onto the chain. M. Davies and D. K. Thomas, J. Phys. Chf,m.,60,767 (1956); L. L. Graham and C. Y. Chang, ibid., 75, 776 (1971). (29) A. R. Katritzky, J. D. Rowe, and S.K. Roy, J. Chem. Sac. B, 758 (1967); 2. Talik, Rocz. Chem., 36, 1313 (1962). (30) A similar effect of 8-methyl substitution in reducing intermolecular association of 4-quinolones has been reported previously and attributed to K hydrogen bonding. P. A. Claret and A. G. Osborne, Spectrosc. Lett., 10, 25 (1977); P. A. Claret and A. G. Osborne, ibid., 9, 157 (1976), and references cited therein. (31) M. D. Joesten and L. J. Schaad, “Hydrogen Bonding”, Marcel Dekker, New York, 1973, pp 279-89; R. B. Homer and C. D. Johnson, “The Chemistry of the Amides”, J. Zabricky, Ed., Interscience, New York. 1970, pp 223-7. (32) 0. Bensaude, M. Chevrier, and J. E. Dubois, Tetrahedron Lett., 222 (1978); J . Am. Chem. Soc , 100, 7055 (1978).
t r i a z o l e ~ and , ~ ~ thio amide^^^ and on the photochemical reactivity of a n i l i d e ~also ~ ~ have been noted. Future determinations of protomeric equilibria, if undertaken to define structure-stability relationships under conditions which could involve self-association, will need to be analyzed carefully in terms of the species actually involved. The extreme dilutions required for observation of monomeric 1-2 and our inability to detect monomeric 17-18 in cyclohexane, along with earlier demonstrations of the phase dependence of such equilibria, may be taken to suggest again that care should be exercised in assignments of relative chemical binding energies of protomers from equilibrium constants in For situations in which association is a serious problem, indirect methods, such as calorimetric approaches,’J4 may be more useful than direct measurement. On the other hand, the present results also show that self-association of 2- and 4-pyridones can be minimized by the choice of solvent. The changes observed in the association energies in different solvents can be attributed to the ability of the solvent to engage in hydrogen bonding which can compete with self-association and to differential solution of the different dipoles of the associated and unassociated Substituents which can interfere with intermolecular hydrogen bonding also reduce the self-association of the hydroxypyridine-pyridone systems. Thus the effect of the 3-carboalkoxy substituent in the association of 12 relative to that of 8 and 10 is explained, in part, by the formation of an intramolecular hydrogen bond as shown in 25 and, in part, by steric repulsion of groups in the 3- and 6-positions of the 2-pyridone dimers. The planar and cyclic structures of the 2-pyridone dimers suggest that substitution would be more hindering for those cases than for the 4-substituted isomers.37 The fact that 6-methyl substitution is effective in reducing association in the 2pyridone system while 2,6-dimethyl substitution is ineffective in the 4-pyridone system bears out that model. However, it is clear that if steric buttressing is made sufficiently severe, as with 2,6-di-tert-butyl substitution, the 4-pyridone system does show reduced self-association. It appears reasonable that the influence on protomeric and association energies of hydroxypyridine-pyridone isomers by the molecular environment extends to the corresponding protomeric equilibrium and associations of the nucleic acid bases. Attempts to assess these biologically important interactions on the basis of protomeric data from aqueous media should be highly suspect. Indeed, the present results extend our earlier concern about the inappropriate extrapolation of structural data between very different envir0nments.l Clearly the thermodynamics of the hydrogen-bonding interactions which are central in the control of many biological processes may depend on the local molecular environment. In summary, the present results show that self-associated species may have protomeric equilibrium constants which are substantially different from those of the unassociated molecules. These cases again illustrate the necessity of consideration of all pertinent data before conclusions about the energies of systems in protomeric equilibrium are (33) H. 0. Sieveking and W. Luttke, Ann. Chim. (Paris), 12, 189 (1977). (34) S.Kubota and M. Uda, Chem. Pharm. Bull., 24, 955 (1975). (35) E. Gentric, J. Lauranson, C. Roussel, and J. Metzer, Tetrahedron Lett., 251 (1977). (36) D. Masilamani, R. 0. Hutchins, and J. Ohr, J . Org. Chem., 41, 3687 (1976). (37) In contrast to the 2-pyridone dimers in which the rings should be in approximately the same plane for the 4-pyridone oligomers, there appears to be little reason for alignment of the rings.
J. Org. Chem., Vol. 45, No. 8,1980 1359
Displacement of Protomeric Equilibria
Scheme IVa
drawn. It is also to be noted that b y proper choice of solvent and high dilutions or by using sterically hindered s y s t e m s monomeric species can be observed. Experimental Section 'H NMR spectra were recorded as solutions in chloroform-d (CDCI,) or dimethyl-d6 sulfoxide (Me2SO-ds),and all chemical shifts are relative to internal tetramethylsilane. Elemental analysis and microgram-quantity weighings were done by Mr. J. Nemeth and associates. Mass spectra were recorded on a Varian MAT CH-5 mass spectrometer by Mr. J. Carter Cook and associates. Cyclohexane tind n-decane were washed with several portions of concentrated sulfuric acid followed by 10% sodium bicarbonate and several washes with water. The solvents were dried over anhydrous magnesium sulfate and distilled from metallic sodium. Distilled in glass chloroform and dichloromethane were passed over basic aluminum oxide and dried only anhydrous magnesium sulfate. Spectrograde solvents were used as received. Compounds 1-2,23-4; 5 -6:' 15-16; 17-18? 19-20,% 21-22,39 and 23-2440have been previously described and were obtained from commercial sources or by standard procedures. Materials used for these studies had satisfactory spectral and analytical properties. Vapor pressure osmometric measurements were carried out on a Mechrolab Model 301A vapor pressure osmometer and on a Knauer vapor pressure osmometer at concentrations as M. The instruments were calibrated with the aplow as propriate solvent and naphthalene as a nonassociating standard. It was also show-n that N-methylpyridones are not associated under the conditions of measurement. Ultraviolet Spectra. Ultraviolet spectra (UV) a t concentrations greater than M were recorded on a Cary 14 spectrophotometer with cells having path lengths from 0.01 to 15 cm. Ultraviolet spectra at concentrations below M were recorded on a variable path length spectrophotomer which was calibrated 275 nm), and 1with naphthalene, 2-methoxypyridine ,,A,( methyl-2-pyridone (A,= 310 nm). A sample of 2-pyridone at 1.3 X 10-5-3 X lo4 M in cyclohexane = 300 (A = 1.6). At with 5-cm cells shows one band with, , ,A 1.5 X lo4 M in 300-cm cells two bands are observed in the spectrum of the pyridone with, ,A a t 300 nm (A = 1.3) and at the two bands have A,, a t 300 278 nm (A = 1.0). At 7.5 X nm (A = 0.70) snd a t 278 nm ( A = 0.8). A t the lowest concentration, W7M the hands are, , ,A at 300 nm (A = 0.23) and at 278 nm (A = 0.3). Variable-temperature studies of the ultraviolet spectrum of 2-pyridone were' carried out in decane in the previously described 15-cm cell.' A solution cf 5 X M 2-pyridone in decane at ambient of 300 nm (A = 0.64). At 100 temperature has a band a t a A,, "C the band centered at, , A = 300 nm has a reduced absorbance of 0.47, and a second band with, X = 275 nm (A = 0.28) appears. The absorbances a t elevated temperature are corrected for absorbances attributed to decomposition of impurities at the given temperature. Spectra recorded at 130,150, and 160 "C show that = 275 nm is predominant. above 130 "C the absorbance at, , ,A The ultraviolet spectrum of a solution allowed to cool to ambient temperature shows only an absorbance a,t , A = 300 nm (A = 0.62) after correction for the impurity absorbances. The solution of 2-pyridone in decane was washed with five 2-mL portions of wat,er, and a spectrum recorded of the water extract = 300 (A = 0.5) identical with shows only an absorbance at, , A the spectrum of a fresh sample of 2-pyridone in water. A spectrum of the washed decane contained the absorbance of the impurities = 260 nm (A -- 0.18). a,t , A I-Methoxy.6-methy1-2-pyridone (6). To 50 mL of dry methanol was added 1.57 g (68.4 mmol) of sodium metal. When reaction was complete, 5.70 g (45.6 mmol) of 4-hydroxy-6methyl-2-pyridone waq added and the mixture heated to reflux, whereupon 25.47 g (1 36.8 mmol) of methyl tosylate was introduced. After 20 h a t reflux, 1he mixture was allowed to cool to room (38) P. Beak. Tetrahedron. 20.831 (1964).and references cited therein. (39) P. Bellinpham, c'. D. Johnson, and A. R. Katritzky, J . Chem. SOC. B , 1226 (1967). (40) H. C. win der Plas and H. J. den Hertog. Recl. Trau. Chim. Pays-Bas, 81, 841 (1962).
R = Me, Et
CH3
30a,b
CH3 A N ' %
I
I
A
H
31
9
a a: (1)n-BuLi, THF, 0 "C; (2) 6 N aqueous H 2 S 0 4 ; ( 3 ) 10% aqueous KOH. b: (CH3),SiI, CHCl3, A . C: HS(CH,),SH, CHC13, A , BF,.OEt,.
temperature, the precipitated sodium tosylate was removed by filtration, and the clear filtrate was poured into 150 mL of 5% aqueous ammonia and stirred for 1 h. The resulting solution was then saturated with sodium chloride and extracted with methylene chloride, and the dried (MgS04)extract was evaporated in vacuo to yield fine white needles. Chromatography on silica gel with a 70:30 ethyl acetate-methanol mobile phase provided three (6.7%), and fractions: 4 (%YO),2,4-dimethoxy-6-methyIpyridine 2-methoxy-l,6-dimethyl-4-pyridone (0.5% ). Recrystallization of 4 four times from acetonitrile provided 1.08 g (18%)of pure 4: mp 176-180 "C41 mp 172-173 "C); 'H NMR 6 2.28 (s, CH3), 3.77 (s,0CH3),5.75 (s,H3and H5); IR 1655 cm-' (C=O);UV A, 225 (t 2600), 285 (5200); mass spectrum (10 eV), m / e 139 (M'). Anal. (C7H9N02)C, H, N. Synthesis. Syntheses of compounds 7, 4, 11, and 13 were carried out as outlined in Schemes IJI-VI. In the synthetic procedures which follow the schemes, the phrase "extractive workup" refers to washing of an organic extract with dilute aqueous acid or base as necessary for the removal of basic or acidic impurities or reagents, respectively, followed by a wash with saturated NaCl solution. 2-Methoxy-3-cyano-6-methylpyridine (27). A dichloromethane slurry of 59.9 g (0.446 mol) of 2643and 69.33 g (0.469 mol) of trimethyloxonium fluoborate was stirred a t room temperature under a dry Nz atmosphere for 48 h. At the end of this time excess 10% aqueous NaOH was added, and the organic phase was separated, washed with saturated aqueous NaCl solution, and dried over K2CO3. The solvent was removed at reduced pressure and the resulting crude product recrystallized from hexaneethanol to afford 54.2 g (83%) of pure 27 as lustrous, white plates: mp 83-84 "C (lit.44mp 81.5 "C); 'H NMR (CC14)6 2.52 (6, 3 H, CH3),4.03 (s, 3 H, OCH3), 6.73 (d, J = 8 Hz, 1 H, H-5), 7.69 (d, J = 8 Hz, 1 H, H-4); IR (Nujol mull) 2222 (C=N), 1122 cm-I (OCHJ. Anal. (C8H8N20)C, H, N. 2-Methoxy-6-methylpyridine-3-carboxaldehyde (28). A solution of 23.05 g (0.156 mol) of the nitrile 27 in dry toluene was cooled to -78 "C and treated dropwise with 23.23 g (0.163 mol) of neat diisobutylaluminum hydride (Ventron). After completion of the addition, the resulting bright yellow solution was allowed to stir at -78 "C for 30 min and then at ambient temperature for 3 h. Excess reducing agent was destroyed by addition of 100 mL of saturated aqueous NH4C1solution followed by stirring of the reaction mixture for 30 min at ambient temperature. The imine produced by the reduction was cleaned by addition of 100 mL of 5% aqueous H2S04to the above mixture followed by stirring for 5 min. Adjustment of the pH to 9 by addition of 10% aqueous KOH solution and extractive workup with toluene followed by ~~
~
(41) The broad melting point appears to be due to the formation of dimorphic crystals from acetonitrile. A remelted sample has a melting point of 180-181 "C. (42) H. M. Woodburn and M. Hellman, Recl. Trau. Chim. Pays-Bas, 70, 813 (1951). (43) L. J. Binovi and H. G. Arlt, Jr., J. Org. Chem., 26, 1656-75 (196lj. (44) R. P. Mariella and A. J. Havlik. J . Am. Chwn. Soc., 74, 1915-6
1360
J. Org. Chem., Vol. 45, No. 8, 1980
Beak e t al.
aCN - a -
Scheme VIa
Scheme V a
CONH;!
0
CH3
b 175 %)
(78%)
CH3
OCti:
27
OCH3
32
/(NxcooH
33
c (26%)_
CY3
OCH3
PhS
33 C02H m
a
o
c
H
-
3
w
I
H
39
d 1940/.)
PhS
34
JJnqco2H 0
PhS
-
e (60%)
H
35
&r2C
6H33
fD H
Ph S
c l f
12
O2CSH 33
OCH3 PhS
-+
/
13
a a: (1)2 equiv of LDA, THF-hexane, - 7 8 ° C ; ( 2 ) 4(pheny1thio)benzaldehyde; ( 3 ) 1.1 equiv of TsOH; H,O, toluene, A ; (4)glacial AcOH, A . b: (1)(CH,),N+OH-, MeOH; ( 2 ) n-C,,H,,OTs, HMPA, 60 "C.
alcohol and 2.45 g (5.41 mmol) of methyltriphenoxyphosphonium iodide at 75 "C for 2 h." After the mixture was cooled to ambient temperature, the very dark reaction mixture was diluted with about 3 volumes of 10% NaOH solution and extracted with several portions of cyclohexane. The usual extractions were followed by removal of the solvent and distillation of the residue in a Kugelrohr apparatus a t 0.5 mmHg with an air-bath temperature of 115-120 "C to afford 170 mg (33%) of 29 as a colorless oil: 'H NMR (CCb) 6 0.93 (br t, J = 6 Hz, 3 H, CH2CH3),1.1Ck1.70 (sextet, J = 6 Hz, 2 H, C-4 CHZCHJ, 2.13 (4, J = 6 Hz, 2 H, =CHCHZ), 3.87 (s, 3 H, OCH3), 5.96 (dt, J = 15, 6 Hz, 1H, =CHCH2), 6.38 (br d, J = 15 Hz, CH=CH), 6.46 (d, J = 8 Hz, H-5), 7.31 (d, J = 8 Hz, 1 H, H-4); IR (neat) 975 cm-' (trans, olefinic CH deformation). 3-[ 1-( E)-Penteny1]-6-methyl-t-pyridone (7). A chloroform solution of 170 mg (0.899 mmol) of 29 and 145 CLL(1.12 mmol) of iodotrimethylsilane was heated a t reflux under a dry N2 atmosphere for 24 h. At the end of this time, the mixture was allowed to cool and then quenched by pouring it into an equal volume of methanol. The solvent was removed a t reduced pressure. The residue was dissolved in dichloromethane, and the usual extractive workup followed. Removal of the solvent gave a yellow solid which was recrystallized from hexane to afford 90 mg (56%)of 7 as a colorless solid mp 102-103 "C; 'H NMR (CCL) 6 0.97 (t, J = 6 Hz, 3 H, CHzCH3),1.49 (sextet, J = 6 Hz, 2 H, C-4 CHZCH,), 2.15 (dt, J = 6, 4 Hz, 2 H, =CHCH&, 2.39 (s, 3 H, 6-CH3), 5.86 (d, J = 8 Hz, 1 H, H-51, 6.25 (d, J = 15 Hz, 1 H, olefinic proton (Y to ring), 6.39 (dt, J = 15,4 Hz, 1H, olefinic proton p to ring), 7.20 (d, J = 8 Hz, 1 H, H-4); IR (Nujol mull) 1650 (lactam C=O), 978 cm-' (trans olefinic CH deformation); UV (CH2Clz)A,, 250 nm ( e 6000), 332 (800). Anal. (CIIHISNO)C, H, N. Mixture of 2-Methoxy-3-pentanoyl-6-methylpyridine (30a) and 2-Ethoxy-3-pentanoyl-6-methylpyridine (30b). A dry THF solution of 5.50 g (36.5 mmol) of a 60:40 mixture of 2methoxy-3-cyano-6-methylpyridine (27)and its 2-ethoxy homologue (prepared analogously to 27 from 26 by using a mixture of trimethyl- and triethyloxonium fluoborate) was cooled to 0 "C and 16.47 mL of 2.44 M n-butyllithium in hexane (40.2 mmol) added dropwise over about 10 min. The resulting very dark red mixture was stirred at 0 "C for 30 min and subsequently a t room temperature for 1 h. The reaction was then cautiously quenched by slow addition of 6 N H2S0,, and the two-phase mixture so produced was heated to 50-60 "C and vigorously stirred for 2 h. The mixture was then made basic by addition of 10% aqueous KOH solution, hexane was added, the layers were separated, and the aqueous phase was extracted twice with THF-hexane. Extractive workup followed by removal of the organic solvent gave
fl:'d33
36
PhS
/
CH3
37 30% K O 2 ,25% aqueous NaOH, EtOH, 50-60 "C. a a: b: (1)10% aqueous KOH; ( 2 ) H,O+. c: (1)2 equiv of LDA, THF-hexane, -78 OC; ( 2 ) 4-(pheny1thio)benzyl chloride; ( 3 ) H,O'. d : (CH,),SiI, CHCl,, room temperature, 18 h. e: (1)(CH,),N'OH-, EtOH; ( 2 ) nC,,H,,OTs, HMPA, 60 "C. f : (CH,O),SO,, K,CO,, DMF, room temperature.
removal of solvent a t reduced pressure gave a slightly yellow oil. Sublimation a t 90 "C and 0.5 mmHg afforded 18.5 g (80%) of 28 as a colorless solid: mp 44-45 "C; 'H NMR (CClJ 6 2.50 (s, 3 H, CH3),4.02 (s, 3 H, OCH3), 6.75 (d, J = 8 Hz, 1 H, H-5), 7.91 (d, J = 8 Hz, 1 H, H-4), 10.21 (s, 1H, CHO); IR (Nujol mull) 2770 (aldehyde CH), 1695 cm-' (aldehyde C=O). Anal. (C,HgN02) C, H, N. 2-Methoxy-3-[ I-( E)-pentenyl]-6-methylpyridine(29). An ethereal solution of n-butylmagnesium iodide was prepared in the usual fashion from 196 mg (8.04"01) of magnesium turnings and 1.23 g (6.70 mmol) of 1-iodobutane. After the solution was cooled to -10 "C, it was treated dropwise with a solution of 1.00 g (6.70 "01) of the aldehyde 28 in 8 mL of ether. The resulting mixture was allowed to stir for 16 h at room temperature and then quenched by addition of a few milliliters of saturated aqueous NH4+Cl-solution. Extractive workup with diethyl ether provided 1.16 g (84%) of the desired secondary carbinol product as a yellow oil. This material was indicated to be 85% pure with a single contaminant of the starting aldehyde 28 by *H NMR. The crude carbinol was dehydrated in a hexamethylphosphoramide (HMPA) solution of 560 mg (2.71 mmol) of the
(45) R. 0. Hutchins, M. G. Hutchins, and C. A. Milewski, J. Org. Chem., 37, 4190-2 (1972).
Displacement of Protomeric Equilibria a reddish brown oil which was then further purified by medium-pressure liquid chromatography on silica gel using 80:20 hexane-ether as the mobile phase. This yielded 2.50 g (33%) of a yellow oil which was shown by 'H NMR to be an 85:15 mixture of 30a and 30b, respectively. 3-Pentanoyl-6-methyl-2-pyridone (31). The mixture of 30a and 30b (2.41 g, 11.63 "01) was heated with 3.02 mL (23.3 mmol) of iodotrimethylsilane a t reflux in dry CHC13 for 16 h under an N2 atmosphere. After a workup similar to that used for 7, crude pyridone 31 was obtained. Recrystallization from aqueous ethanol gave 1.64 g (73%) of 31 as cream-colored crystals: mp 183-185 OC; 'H NMR (CHC13) 6 0.94 (br t, J = 6 Hz, 3 H, CHzCH3), 1.20-1.90 (m, 4 H, CHzCHzCH2CH3),2.47 (s, 3 H, 6-CH3), 3.13 (br t, J = 6 Hz, 2 H, COCH2),6.23 (d, J = 8 Hz, 1 H, H-5), 8.17 (d, J = 8 Hz,1H, H-4), 13.5 (br s, 1H, NH); IR (Nujol mull) 1669 (ketone C=O), 1645 cm-' (lactam C=O). 2- (6-Methy1-2-pyridon-3-y1)-2-n -butyl-1,3-dit hiolane (9). Pyridone ketone 31 (0.531 g, 2.75 mmol) was heated in refluxing chloroform for 24 h with 1.30 g (13.76 mmol) of ethanedithiol in the presence of a catalytic amount of boron trifluoride etherate. Extractive workup followed by removal of solvent provided a slightly yellow solid. Recrystallization from acetonitrile afforded 467 mg (63%) of the dithioketal9 as colorless, fibrous needles: mp 134-135 "c'; 'H NMR (CDClJ 6 0.84 (br t, J = 6 Hz, 3 H, CH2CH3),1.22 (m, 4 H, CHzCH2CH3),2.33 (s, 3 H, 6-CH3), 2.59 (br t, 6 Hz, 2 H , S2-C--CH2), 3.18 (m, A2Bz,4 H, (SCH,),), 5.97 (d, J = 8 Hz, 1 H, H-5), 7.83 (d, J = 8 Hz, 1 H, H-4), 13.0 (br s, 1H, NH);IR (Nujol mull) 1642 cm-' (lactam C=O); UV (CH2C1,) ,X 237 nm (c 6100), 310 (10000). Anal. (CI3Hl9NOS2)C, H, N, S. 2-Methoxy-6-methylpyridine-3-carboxamide (32). To a solution of 4.86 g (32.8 mmol) of 27 in a mixture of 40 mL of 95% ethanol and 15 mL of 25% aqueous NaOH was added with stirring 16.73 mL (164 mmol) of 30% HzOz in a single portion. The reaction temperature was held below 60 "C by occasional cooling in an ice bath until the initial moderately strong exotherm and accompanying O2 evolution had subsided. The temperature of the mixture was then held a t 55 "C for 3 h. After this time the mixture was allowed to cool and was neutralized by addition of concentrated HC1, and the precipitated product was then collected by filtration. Recrystallization of this crude product from water gave 3.90 g (78%) of 32 as a colorless solid: mp 129-130 "C; 'H NMR (CDClJ 6 2.50 (s, 3 H, 6-CH3), 4.10 (s, 3 H, OCH3), 6.85 (d, J = 8 Hz, 1 H, H-5), 8.37 (d, J = 8 Hz, 1 H, H-4); IR (Nujol mull) 3425, 3135 (amide NH), 1667 cm-' (C=O). Anal. (C8HioNzOz) C, H , N. 2-Methoxy-6-methylpyridine-3-carboxylic Acid (33). Heating 3.74 g (2.25 mmol) of 32 a t reflux in 10 mL of 10% aqueous KOH for 3 h followed by acidification to pH 4 gave a flocculent precipitate of 33, as 2.83 g (75%) of an analytically pure white solid: nip 114--115 "C; 'H NMR (CDCl,) 6 2.50 (s, 3 H, 6-CH3), 4.15 (h, 3 H, OCH3),6.92 (d, J = 8 Hz, 1 H, H-5), 8.30 (d, J = 8 Hz, I H, H-4); IR (Nujol mull) 3300-2500 (br, COOH OH), 1686 cm (C=O). Anal. (C8H9NO3)C, H, N. 2-Methoxy-6-[2-(4'-phenylthio)phenethyl]pyridine-3carboxylic Acid (34). A THF-hexane solution of lithium diisopropylamide (LDA) was prepared at -78 "C from 7.46 g (73.7 mmol) of diisopropylamine and 30.20 mL of 2.44 M n-butyllithium in hexane (73.7 mmol). To this was added dropwise, at -78 "C, a T H F solution of the acid 33 (5.87 g, 35.1 mmol), giving a bright yellow-orange solution. After completion of the addition, the mixture was allowed to stir a t -78 "C for 30 min, whereupon a solution of 4-(pheny1thio)benzyl c h l ~ r i d e(8.24 ~ ~ , g, ~ 35.1 mmol) was added in a single portion and the cooling bath removed. After being stirred for 5 h a t room temperature, the reaction was quenched by addition of a few drops of water. The yellow rolution was acidified to pH 4 by addition of 10% HC1 solution and hexane added. Extractive workup of the resulting solution provided a yellow oil. When this oil was cooled to -20 "C for 24 h, yellow crystals were obtained; these were isolated by filtration and washed well with benzene to afford 4.4 g of crude 34. Two recrystallizations from benzene-hexane and three from methanol gave 3.28 g (26%) of pure 34, mp 127-128
'
(46) G. Cavallini, E. Massarani, D. Nardi, L. Mauri, and F. Tencovi, Farmaco, Ed. Sci., 19, 964-71 (1964).
J . Org. Chem., Vol. 45, No. 8,1980 1361 "C. The crude product oil could also be purified by mediumpressure liquid chromatography on silica gel, affording essentially the same yield of the desired product. The major side product in this reaction was identified as 1,2-bis[4-(phenylthio)phenyl]ethane. For 34: 'H NMR (CDC13) 6 3.07 (br s, 4 H, Ar(CH,),-pyr), 4.14 (s, 3 H, OCH3), 6.88 (d, J = 8 Hz, 1 H, H-5 of pyridine ring), 7.W7.40 (m, 9 H, Ar H of Ar-S-Ar moiety), 8.31 (d, J = 8 Hz, 1 H, H-4 of pyridine ring); IR (Nujol mull) 3400-2100 (br) (COOH OH), 1689, 1667 cm-' (COOH C=O). Anal. (Cz1HI9NO3S)C, H, N, S. 6-[2-(4'-Phenylthio)phenethyl]-2-pyridone-3-carboxylic Acid (35). A dry chloroform solution of 3.28 g (8.98 mmol) of 34 and 2.69 mL (20.2 mmol) of iodotrimethylsilane was stirred under a dry N2 atmosphere a t room temperature for 18 h. The resulting bright red solution was poured into excess methanol and the solvent removed in vacuo from that mixture. The residue was taken up in 95% ethanol and the solution treated with 10% aqueous NaHS03 until the color of I2 was fully dissipated. The mixture was then heated to the boiling point and water added to dissolve some precipitated inorganic salts. As the mixture cooled, colorless crystals of product separated which were collected by filtration and air-dried to provide 2.95 g (94%) of analytically pure 35 as colorless crystals: mp 189-191 "C; 'H NMR (Me&O-d,) 6 2.97 (s, 4 H, Ar-(CH2)2-pyr), 6.51 (d, J = 8 Hz, 1 H, H-5 of pyridone ring), 7.29 (m, 9 H , Ar H of Ar-S-Ar), 8.26 (d, J = 8 Hz, 1H, H-4 of pyridone ring); IR (Nujol mull) 3300-2600 (br) (COOH OH), 1739 (COOH C=O), 1642 cm-' (lactam C=O). Anal. (CzoHi7NO3S) C, N, S. n -Hexadecyl 6-[2-(4'-Phenylthio)phenethyl]-2-pyridone3-carboxylate (12). The acid 35 (2.95 g, 8.39 mmol) was dissolved in a minimum amount of hot methanol, and 2 drops of 1%ethanolic phenolphthalein were added. This mixture was then titrated to the end point with methanolic tetramethylammonium hydroxide (Aldrich). The alcoholic solvent was then removed in vacuo and replaced with 75 mL of dry HMPA. Solid n-hexadecyl tosylate (3.50 g, 8.81 mmol) was added and the mixture stirred at 60 "C for 24 h. At the end of this time the mixture was poured into 400 mL of ice water and the resulting cream-colored emulsion worked up by extracting with THF-benzene to afford an oil. Purification of this oil was accomplished by medium-pressure liquid chromatography (LC) on silica gel employing 90/8/2 chloroform/ hexane/ethanol as the mobile phase. Crystallization of the product fractions from hexane gave 2.82 g (60%) of analytically pure 12: mp 65.5-66.5 "C; 'H NMR (CDCl,) 6 0.86 (br t, J = 6 Hz, 3 H, terminal CH3 of hexadecyl chain), 1.26 (br s, 28 H, interior methylenes of the hexadecyl chain), 2.98 (br s, 4 H, Ar-(CH2)2-pyr), 4.23 (br t, J N 6 Hz, 2 H, CO,CH,), 6.15 (d, J = 8 Hz, 1 H, H-5 of pyridone ring), 7.21 (br s, 9 H, Ar H of Ph-S-Ph), 8.07 (d, J = 8 Hz, 1 H, H-4 of pyridone ring); IR (Nujol mull) 1748 (ester C=O), 1647 (lactam C=O), 1269, 1121 215 nm ( t 23600), 235 cm-' (ester CO); UV (cyclohexane) A,, (19 loo), 254 (16400), 300 (16400); mass spectrum (70 eV) m / e (% of base) 577 (9.45),576 (24.21),575 (M', 61.4), 333 (41.3), 224 (12.9), 201 (20.21), 200 (100). Anal. (C36H49N03S) C, H, N, S. n -Hexadecyl2-Methoxy-6-[ 2- (4'-pheny1thio)phenet hyllpyridine-3-carboxylate (36) a n d n -Hexadecyl 6-[2-(4'Phenylthio)phenethyl]-1-methyl-2-pyridone-3-carboxylate (37). A mixture of 198 mg (0.34 mmol) of 12, 2.5 g (18 mmol) of potassium carbonate, and 0.5 mL (0.5 mmol) of dimethyl sulfate was stirred for 18 h at room temperature in dimethylformamide solution. At the end of this time, the reaction mixture was diluted with water and worked up extractively with diethyl ether to provide an oil which NMR indicated to be a 2:3 mixture of 36 and 37, respectively. These were separated into two bands by preparative TLC on silica gel using 1:l hexane-ether as the developer. The high-R, component was eluted from the plate with chloroform. After removal of the solvent, an oil was obtained which was crystallized from ethyl acetate to afford 51 mg (25%) of 36: mp 3%40 "C; 'H NMR (CC14)6 0.92 (br t, J = 6 Hz, 3 H, terminal CH3 of hexadecyl chain), 1.28 (br s, 28 H, interior methylenes of hexadecyl chain), 3.00 (br s, 4 H, Ar-(CH,),-pyr), 3.95 (s, 3 H, OCH3), 4.19 (br t, J = 6 Hz, 2 H , CO,CH,), 6.60 (d, J = 8 Hz, 1 H, H-5 of pyridone ring), 7.15 (br s, 9 H, Ar H of Ar-S-Ar), 7.93 (d, J = 8 Hz, 1 H, H-4 of pyridone ring); UV (CH,Cl2) A,, 229 nm (sh), 259 (c 7600), 284 (8200). Anal. Calcd for C37HbiNO3S:
1362
J . Org. Chem. 1980,45,1362-1366
C, 75.34; H, 8.71. Found: C, 74.66; H, 8.99. The component of low Rf was eluted with ethyl acetate; reduction in volume of the resulting solution gave 65 mg (32%) of 37: mp 59-60 "C; 'H NMR (CC14) 6 0.96 (br t, J = 6 Hz, 3 H, terminal CH3 of hexadecyl chain), 1.33 (br s, 28 H, interior methylenes of hexadecyl chain), 2.90 (br s, 4 H, Ar-(CHz)z-pyr), 3.47 (s, 3 H, NCH,), 4.16 (br t, J = 6 Hz, 2 H , C02CHz),5.86 (d, J = 8 Hz, 1 H, H-5 of pyridone ring), 7.23 (br s, 9 H, Ar H of Ar-S-Ar), 7.80 (d, J = 8 Hz, 1 H, H-4 of pyridone ring); UV (CH2C12),A, 245 nm (c 7600), 273, 345 (6300). Anal. (C3&1N03S) C, H. 6 4 (4'-Phenylthio)-(E)-styryl]-2-pyridone-3-carboxylic Acid (39). The LDA dilithiation of 4.57 g (27.3 mmol) of carboxylic acid 38 was performed in a manner analogous to that employed for the preparation of 34. The dilithiated species was then trapped by addition a t -78 "C of a T H F solution of 5.86 g (27.3 mmol) of 4-(phenylthio)ben~aldehyde.~~,~~ The reaction mixture was allowed to warm to room temperature and stirred for 2 h. After the mixture was quenched with a few drops of water and acidified to pH 3 with 10% aqueous HCl, extractive workup provided a yellow solid which was indicated by 'H NMR to be composed of 85% of the desired secondary carbinol. This material was not purified but was, instead, dehydrated directly by heating with 6.0 g (31.5 mmol) of toluenesulfonic acid monohydrate in toluene a t reflux with continuous removal of the water formed. The orange solid obtained was taken up in hot glacial acetic acid and decolorized with carbon. The solids obtained on cooling were washed with water followed by recrystallization of the crude material from glacial acetic acid to give 2-pyridone 39. The yield of yellow plates, mp 270-271 "C dec, was 7.1 g (74% overall from 38): 'H NMR (MeaSO-ds) 6 6.95 (d, J = 8.4 Hz, 1 H, pyridone H-5), 7.05 (d, J = 15.6 Hz, 1 H, olefinic proton a to pyridone ring), 7.40 (AA'BB' q, J = 8.4 Hz, 4 H, disubstituted Ar H), 7.40 (s, 5 H, 5 Ar H), 7.78 (d, J = 15.6 Hz, 1 H, olefinic H (Y to phenyl ring), 8.30 (d, J = 8.4 Hz, 1H, pyridone H-4); IR (Nujol mull) 34W2400 (br, COOH OH), 1742 (COOH C=O), 1632 (lactam C=O), 973 (trans olefinic CH deformation); mass spectrum (70 eV), m/e ( % of base) 351 (8.61),350 (24.76), 349 (M', 100). Anal. (C&Il5NO3S) C, H, N, S. (47) H. H. Szmant, J. M. Segedi, and J. Dudek, J. Org. Chem., 18, 745-7 (1953).
n -Hexadecyl6-[(4'-Phenylthio)-(E)-styryl]-2-pyridone3-carboxylate (13). Esterification of 4.80 g (13.7 mmol) of 39 was accomplished by alkylation of the corresponding tetramethylammonium salt with 5.74 g (14.4 mmol) of hexadecyl tosylate in HMPA in a manner analogous to that employed for the corresponding saturated system 35. The crude product so obtained was purified by medium-pressure LC on silica gel employing 7012515 chloroform/hexane/ethyl acetate as the mobile phase. The fractions containing 13 were combined, and the solvent was removed a t reduced pressure. The resulting yellow solid was crystallized from hexane to afford 4.00 g (51% ) of pure 13 as bright yellow, matted needles: mp 135-136 "C; 'H NMR (CDC13)6 0.87 (br t, J = 6 Hz, 3 H, terminal CH3 of hexadecyl chain), 2.29 (br s, 38 H, interior methylenes of hexadecyl chain), 4.27 (t, J = 6 Hz, 2 H, C02CH2),6.57 (d, J = 8.4 Hz, 1 H, pyridone H-5),6.86 (d, J = 15.4 Hz, 1 H, CH=CHCsH4C6H5), 7.10-7.73 (m, 9 H, Ar H of AI-S-Ar), 7.85 (d, J = 15.4 Hz, 1 H, CH=CHC6H4SC6H6), 8.13 (d, J = 8.4 Hz, 1 H, pyridone H-4); IR (Nujol mull) 1751, 1736 (ester C=O), 1631 (lactam C=O), 1282, 1149 (ester CO), 989 cm-I (trans olefinic CH deformation); UV (cyclohexane) A, 219 nm (c 15500), 254 (14400), 373 (35300); mass spectrum (70 eV), m/e (70of base) 575 (17), 574 (40.3), 573 (M'., 100), 332 (64.7). Anal. (&H4,N03S) C, H, N, S.
Acknowledgment. We are grateful to the National Science Foundation and the National Institutes of Health for support of this work. Registry No. 1, 72762-00-6;2, 142-08-5;3,73018-09-4; 4, 1722861-4; 5 , 72917-96-5; 6, 72982-87-7; 7, 72917-97-6; 8, 73035-73-1; 9, 72917-98-7; 10, 72983-37-0; 11, 72917-99-8; 12, 73035-74-2; 13, 72918-00-4;14,73035-75-3;15, 73018-10-7;16,2637-34-5;17,626-64-2; 18, 108-96-3; 19, 17368-12-6; 20, 17228-67-0; 21, 13603-44-6; 22, 7516-31-6; 23, 72918-01-5; 24,72918-02-6; 26, 4241-27-4; 27, 7291803-7; 28, 72918-04-8;29,72918-05-9;30a, 72918-06-0;30b, 72918-07-1; 31, 72918-08-2; 32, 72918-09-3; 33, 72918-10-6; 34, 72918-11-7; 35, 72918-12-8; 36, 72918-13-9; 37, 72918-14-0; 38, 38116-61-9; 39, 72918-15-1;4-hydroxy-6-methyl-2-pyridone, 3749-51-7; 2,4-dimethoxy-6-methylpyridine, 40334-96-1; 2-methoxy-l,6-dimethyl-4pyridone, 40334-98-3; 2-ethoxy-3-cyano-6-methylpyridine, 54957-812; 4-(pheny1thio)benzyl chloride, 1208-87-3;1,2-bis[4-(phenylthio)phenyllethane, 72918-16-2;n-hexadecyl tosylate, 6068-28-6;4-(phenylthio)benzaldehyde, 1208-88-4.
r-Complexed P-Arylalkyl Derivatives. 6. Effect of Electron-Withdrawing Substituents on the Acetolysis of 2-[~-(Aryl)chromium tricarbonyl]-2-methyl-l-propyl Methanesulfonates' Robert S. Bly,* Ester K. Ni, Albert K. K. Tse, and Easley Wallace Department of Chemistry, University of South Carolina, Columbia, South Carolina 29208 Received September 18, 1979 The a-(arenekhromium tricarbonyl complexes of m-methoxy- and p-chloro-substituted 2- [ a-(pheny1)chromium tricarbonyl]-2-methyl-l-propyl(neophyl) methanesulfonates have been prepared and their acetolysis rates determined. A t 99.5 "C, the complexes are, respectively, 1.1 and 1.6 times as reactive as their noncomplexed counterparts. The p-chloroneophyl complex yields, after oxidative decomplexation of the product mixture with acetate, 34% 3-(p-chlorophenyl)-2-methyl-l-propene, and Ce(IV), 54% 3-(p-chlorophenyl)-2-methyl-2-propyl 12% l-(p-chlorophenyl)-2-methyl-l-propene. No nonaryl-migrated products are observed. The acetolysis rates of p-methoxy-, m-methoxy-, p-methyl-, m-methyl-, and p-chloroneophyl complexed and noncomplexed methanesulfonates at 99.5 "C are well correlated by the Yukawa-Tsuno relations: log (k/ko)compler= -3.39[a + 0.47(a+ - a)] - 0.03 and log (k/ko)non,, lex = -1.97[a + 0.18(u' - a)] - 0.16. The meaning of these correlations is discussed, and it is concluded that in arfdition to its strong inductive electron withdrawal, a-tricarbonylchromium acts amphoterically to donate or withdraw electrons by resonance. From a comparison of the relative acetolysis rates of the p- and m-methoxy complexes, it is suggested that the a-tricarbonylchromium probably does not act via direct d-orbital participation to accelerate the solvolysis rates of the complexes.
In a previous paper in this series2 we reported that the acetolysis rates at 75 "C of the r-(arenelchromium tri0022-3263/80/1945-1362$01.00/0
carbonyl complexes of 2-phenyl-2-methyl-1-propyl (neophyl) and p-methoxy-, p-methyl-, and m-methylneophyl 0 1980 American Chemical Society
